Environmental chemicals are significant risk factors for atherosclerotic vascular disease, but molecular mechanisms of atherogenesis have not been elucidated with certainty. Research in this laboratory during the previous funding cycle established that transcriptional deregulation of gene expression by aromatic hydrocarbons is a critical event in the induction of proliferative (i.e. atherogenic) phenotypes in vascular smooth muscle cells (vSMCs). Challenge with atherogenic hydrocarbons was shown to alter redox status and trigger a complex cellular response that culminates in modulation of vascular gene expression. Of particular relevance was the finding that functional interactions between aryl hydrocarbon receptor (AhR) and proteins that bind the antioxidant/electrophile response element (AREBpRE) are central to the loss of transcriptional control in hydrocarbon-treated cells. On the basis of these findings our unifying hypothesis is that deregulation of gene expression in vSMCs by aromatic hydrocarbons involves complex interactions between activated ARE/EpRE binding proteins, AhR, and co-regulators of transcription during the course of the atherogenic response. To test this hypothesis, experiments are proposed to purify and clone AREJEpRE binding proteins from vascular tissue following chemical injury, evaluate the role of HMG-1 (Y) as a co-regulator of ARFJEpRE-regulated gene transcription in vSMCs, and characterize promoter-specific patterns of trans-regulation in vSMCs. These studies will enable us to define the role of ARE/EpRE binding proteins in oxidant-induced atherogenesis and identify critical transacting factors involved in the atherogenic response to environmental injury.
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